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Neuroscience research has made immense progress over the last decade, but our understanding of the brain remains fragmented and piecemeal: the dream of probing an arbitrary brain region and automatically reading out the information encoded in its neural activity remains out of reach. In this work, we build towards a first foundation model for neural spiking data that can solve a diverse set of tasks across multiple brain areas. We introduce a novel self-supervised modeling approach for population activity in which the model alternates between masking out and reconstructing neural activity across different time steps, neurons, and brain regions. To evaluate our approach, we design unsupervised and supervised prediction tasks using the International Brain Laboratory repeated site dataset, which is comprised of Neuropixels recordings targeting the same brain locations across 48 animals and experimental sessions. The prediction tasks include single-neuron and region-level activity prediction, forward prediction, and behavior decoding. We demonstrate that our multi-task-masking (MtM) approach significantly improves the performance of current state-of-the-art population models and enables multi-task learning. We also show that by training on multiple animals, we can improve the generalization ability of the model to unseen animals, paving the way for a foundation model of the brain at single-cell, single-spike resolution.

Latent dynamics models have emerged as powerful tools for modeling and interpreting neural population activity. Recently, there has been a focus on incorporating simultaneously measured behaviour into these models to further disentangle sources of neural variability in their latent space. These approaches, however, are limited in their ability to capture the underlying neural dynamics (e.g. linear) and in their ability to relate the learned dynamics back to the observed behaviour (e.g. no time lag). To this end, we introduce Targeted Neural Dynamical Modeling (TNDM), a nonlinear state-space model that jointly models the neural activity and external behavioural variables. TNDM decomposes neural dynamics into behaviourally relevant and behaviourally irrelevant dynamics; the relevant dynamics are used to reconstruct the behaviour through a flexible linear decoder and both sets of dynamics are used to reconstruct the neural activity through a linear decoder with no time lag. We implement TNDM as a sequential variational autoencoder and validate it on simulated recordings and recordings taken from the premotor and motor cortex of a monkey performing a center-out reaching task. We show that TNDM is able to learn low-dimensional latent dynamics that are highly predictive of behaviour without sacrificing its fit to the neural data.

Modern recording technologies now enable simultaneous recording from large numbers of neurons. This has driven the development of new statistical models for analyzing and interpreting neural population activity. Here we provide a broad overview of recent developments in this area. We compare and contrast different approaches, highlight strengths and limitations, and discuss biological and mechanistic insights that these methods provide.

Current autoencoder-based disentangled representation learning methods achieve disentanglement by penalizing the (aggregate) posterior to encourage statistical independence of the latent factors. This approach introduces a trade-off between disentangled representation learning and reconstruction quality since the model does not have enough capacity to learn correlated latent variables that capture detail information present in most image data. To overcome this trade-off, we present a novel multi-stage modeling approach where the disentangled factors are first learned using a penalty-based disentangled representation learning method; then, the low-quality reconstruction is improved with another deep generative model that is trained to model the missing correlated latent variables, adding detail information while maintaining conditioning on the previously learned disentangled factors. Taken together, our multi-stage modelling approach results in a single, coherent probabilistic model that is theoretically justified by the principal of D-separation and can be realized with a variety of model classes including likelihood-based models such as variational autoencoders, implicit models such as generative adversarial networks, and tractable models like normalizing flows or mixtures of Gaussians. We demonstrate that our multi-stage model has higher reconstruction quality than current state-of-the-art methods with equivalent disentanglement performance across multiple standard benchmarks. In addition, we apply the multi-stage model to generate synthetic tabular datasets, showcasing an enhanced performance over benchmark models across a variety of metrics. The interpretability analysis further indicates that the multi-stage model can effectively uncover distinct and meaningful features of variations from which the original distribution can be recovered.

State-of-the-art models for high-resolution image generation, such as BigGAN and VQVAE-2, require an incredible amount of compute resources and/or time (512 TPU-v3 cores) to train, putting them out of reach for the larger research community. On the other hand, GAN-based image super-resolution models, such as ESRGAN, can not only upscale images to high dimensions, but also are efficient to train. In this paper, we present not-so-big-GAN (nsb-GAN), a simple yet cost-effective two-step training framework for deep generative models (DGMs) of high-dimensional natural images. First, we generate images in low-frequency bands by training a sampler in the wavelet domain. Then, we super-resolve these images from the wavelet domain back to the pixel-space with our novel wavelet super-resolution decoder network. Wavelet-based down-sampling method preserves more structural information than pixel-based methods, leading to significantly better generative quality of the low-resolution sampler (e.g., 64x64). Since the sampler and decoder can be trained in parallel and operate on much lower dimensional spaces than end-to-end models, the training cost is substantially reduced. On ImageNet 512x512, our model achieves a Fr\'echet Inception Distance (FID) of 10.59 -- beating the baseline BigGAN model -- at half the compute (256 TPU-v3 cores).

Determining the positions of neurons in an extracellular recording is useful for investigating functional properties of the underlying neural circuitry. In this work, we present a Bayesian modelling approach for localizing the source of individual spikes on high-density, microelectrode arrays. To allow for scalable inference, we implement our model as a variational autoencoder and perform amortized variational inference. We evaluate our method on both biophysically realistic simulated and real extracellular datasets, demonstrating that it is more accurate than and can improve spike sorting performance over heuristic localization methods such as center of mass.

Reliable spike detection and sorting, the process of assigning each detected spike to its originating neuron, is an essential step in the analysis of extracellular electrical recordings from neurons. The volume and complexity of the data from recently developed large scale, high density microelectrode arrays and probes, which allow recording from thousands of channels simultaneously, substantially complicate this task conceptually and computationally. This chapter provides a summary and discussion of recently developed methods to tackle these challenges, and discuss the important aspect of algorithm validation, and assessment of detection and sorting quality.